1-Chlorosulphonyl-2,3,4,10-tetrahydro-1H-chromeno[3,4-c]azet-2-one

ABSTRACT

A process is disclosed for producing imidazolidone intermediates from 2H-chromene. The intermediates are useful for synthesizing biotin.

This is a continuation of application Ser. No. 324,327 filed Nov. 23,1981, now abandoned, which in turn is a division of Ser. No. 246,839,filed Mar. 23, 1981, now U.S. Pat. No. 4,322,360, which in turn is adivision of Ser. No. 135,796, filed Mar. 31, 1980, now U.S. Pat. No.4,284,788.

SUMMARY OF THE INVENTION

The invention concerns a process for producing imidazolidoneintermediates useful in the synthesis of biotin.

In the process of the invention, 2H-cumene is converted via variousintermediates to a compound of the formula: ##STR1## wherein R⁴ ishydrogen. Compound I then is converted into its alkali metal salt,preferably its lithium salt, and selectively reduced to a compound ofthe formula: ##STR2## wherein R¹ is hydrogen. Compound II then isoxidized to a compound of the formula: ##STR3## wherein R¹ is as above.Compound III then is reduced to a compound of the formula: ##STR4##wherein R¹ is as above, R² is hydrogen; and R³ is lower alkyl oraralkyl, which in turn is converted to a compound of the formula:##STR5## wherein R¹ and R³ are as above and R^(2a) is organosulphonyl.Compound IVa is treated with a sulphide to form a biotin ester of theformula: ##STR6## wherein R³ is as above, which then is hydrolyzed tobiotin of the formula: ##STR7##

If desired either compound II, III or IV wherein R¹ is hydrogen can beconverted to a corresponding compound wherein R¹ is a nitrogenprotecting group.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a process for manufacturing imidazolidonederivatives which are suitable as intermediates for producing biotin.The invention also concerns novel intermediates in this process.

As used herein, alkyl connotes straight or branched chain saturatedaliphatic hydrocarbon groups of 1 to 20 carbon atoms. Lower alkyldenotes alkyl groups of 1 to 6 carbon atoms, such as methyl, ethyl,propyl, isopropyl, butyl and like. Methyl is preferred.

Aryl denotes mononuclear aromatic hydrocarbon groups such as phenyl andthe like which can be unsubstituted or substituted in one or morepositions with halogen, nitro, lower alkylenedioxy, lower alkyl or loweralkoxy. Aryl also denotes polynuclear aromatic groups such as napthyl,anthryl, phenanthryl, azulyl and the like which can be unsubstituted orsubstituted with one or more of the aforementioned substituents.

Aralkyl connotes a group comprising aryl and alkyl moieties as definedhereinbefore. Examples are benzyl and alpha-lower alkyl substitutedbenzyls (e.g., cumyl).

Alkali metals include lithium, sodium, potassium and rubidium. Alkalineearth metals include barium, magnesium, calcium and strontium.

Halogen denotes fluorine, chlorine, bromine and iodine. Halide connotesfluoride, chloride, bromide and iodide.

Alkanol denotes alcohol derivatives of alkyl groups. Lower alkanols arealkanol groups of 1 to 6 carbon atoms. Examples of lower alkanols aremethanol, ethanol, propanol, isopropanol, butanol and the like.

Aralkanols denote alcohol derivatives of aralkyl moieties. Examples arebenzyl alcohol, cumyl alcohol and the like.

Organosulphonyl denotes lower alkyl sulphonyl groups, arylsulphonylgroups and aralkylsulphonyl groups. Examples are methanesulphonyl,toluenesulphonyl and benzenesulphonyl.

Nitrogen protecting groups are conventional nitrogen protecting moietiesutilized in biotin chemistry. Examples are aralkyl (e.g., benzyl), allyl(i.e., --CH₂ CH═CH₂) and the like.

In the pictorial representations of the compounds of this application, asolid tapering line ( ) indicates a substituent in the beta-orientation(above the plane of the molecule) and a dashed line ( ) indicates asubstituent which is in the alpha-orientation (below the plane of themolecule).

In accordance with one aspect of the invention, biotin of the formula:##STR8## is produced from a compound of the formula: ##STR9## wherein R⁴is hydrogen, by the following reaction scheme: ##STR10## wherein R¹ ishydrogen or a nitrogen protecting group; R² and R⁴ each are hydrogen;R^(2a) is organosulphonyl; and R³ is lower alkyl or aralkyl.

In accordance with Reaction Scheme 1, compound I is reduced to compoundII via a corresponding alkali metal salt of compound I.

Compound I is converted into its alkali metal salt such as its lithiumsalt, by any conventional technique for forming alkali metal salts fromits corresponding amidazolidones. For example, compound I is reactedwith an amide (e.g., lithium diisopropylamide) in a lower alkylaminesolvent (e.g., ethylamine) to yield the desired salt. Although notcritical, the reaction temperature generally is chosen according to theboiling point of the amine solvent.

As a further illustration, compound I is converted to its alkali metalsalt, such as its potassium salt, by treatment with potassium tert.butoxide.

The alkali metal salt of compound I is then converted to compound II ina one step or a two step reduction process.

The one step reduction of compound I to compound II conveniently iscarried out using lithium in a lower alkylamine solvent such as amonoalkylamine or a dialkylamine. Ethylamine, dimethylamine or theirmixtures are preferred solvents. The one step reduction is convenientlycarried out while heating at reflux (i.e., at the boiling point of theamine). Reaction times of several hours (e.g., 14 hours) are required.

The first step in the two-step reduction of compound I to compound II iscarried out using lithium in liquid ammonia thus obtaining thecorresponding octahydro compound of compound I. In the second step, theoctahydro compound is catalytically hydrogenated to give decahydrocompound II wherein R¹ is hydrogen.

Compound II is then oxidized to compound III by any conventionaloxidizing technique.

The oxidation of compound II to compound III can be carried out in oneor two steps.

Illustratively, a one step (direct) oxidation of compound II to compoundIII can be carried out using chromic acid in acetone as the oxidatingagent.

The direct oxidation can also be carried out using an organic peracid(e.g., peracetic acid, perbenzoic acid, a halogenated perbenzoic acidsuch as m-chloroperbenzoic acid, trifluoromethylperbenzoic acid ormonoperphthalic acid). Such peracids preferably are used in amounts ofseveral equivalents.

The direct oxidation of compound II to compound III can also be carriedout using an appropriate oxide such as ruthenium dioxide.

In the two-step oxidation of compound II to compound III, firstlycompound II is oxidized to its corresponding dihydroxy compound andsecondly this dihydroxy compound is oxidized to compound III.

Illustratively, the first step of this two-step oxidation is carried outwith a peracid (e.g., peracetic acid, perbenzoic acid, a halogenatedperbenzoic acid such as m-chloroperbenzoic acid,trifluoromethylperbenzoic acid or monoperphthalic acid). The peracidpreferably is used in equivalent amounts.

The second step of the two-step oxidation is carried out using sodiumperiodate. Instead of sodium periodate, lead tetraacetate can also beused as the oxidizing agent. If desired, the dihydroxy compound formedin the first oxidation step need not be isolated.

Compound III is then selectively reduced to compound IV.

The reduction of a compound III to compound IV can be carried out usinga metal borohydride such as an alkali metal borohydride (e.g., sodiumborohydride, potassium borohydride or lithium borohydride) or using zincborohydride. Sodium borohydride is the preferred reducing agent.

The reduction of compound III to compound IV preferably is carried outin the presence of an organic solvent which is capable of bringing aboutan ester formation (i.e., substituent R³ of compound IV is lower alkylor aralkyl, preferably benzyl). Suitable solvents are lower alkanol oraralkanol. Methanol and benzyl alcohol are preferred solvents.

Although temperature is not critical, the reduction can be carried outat room temperature (about 23° C.) or at somewhat elevated temperatures(about 23° C. to about 50° C.). Elevated temperatures are convenientwhen zinc borohydride is used as the reducing agent.

If desired, R¹ of either compound II, III or IV can be converted fromhydrogen to a nitrogen protecting group. Any known manner for addingnitrogen protecting groups onto imidazolidones can be utilized. Forexample, compound II, III or IV wherein R¹ is hydrogen can be reactedwith an aralkyl halide (e.g., benzyl chloride) or an allyl halide toform corresponding compounds wherein R¹ is a nitrogen protecting group.

In accordance with the above procedure, Compound II wherein R¹ is anitrogen protecting group then can be oxidized to compound III whereinR¹ is a nitrogen protecting group which in turn can be reduced tocompound IV wherein R¹ is a nitrogen protecting group.

Compound IV wherein R¹ is hydrogen or a nitrogen protecting group and R²is hydrogen is converted to compound IVa wherein R¹ is as above andR^(2a) is organosulphonyl. This conversion can be carried out byreacting compound IV with a suitable sulphonic acid halide (e.g.,methanesulphonyl chloride, toluenesulphonyl chloride or benzenesulphonylchloride). A tertiary amine base (e.g., pyridine and triethylamine)preferably is used as the solvent in this reaction. Although temperatureis not critical, the reaction is generally carried out at a temperaturebetween about -10° C. and about room temperature (about 23° C.).

Compound IVa then is converted into biotin ester V by treatment with asulphide. Suitable sulphides are alkali metal sulphides and alkalineearth metal sulphides. Sodium sulphide is preferred. The conversion ofcompound IVa to compound V conveniently is carried out in dimethylformamide or hexamethylenephosphoric acid triamide as the solvent. Thesulphide preferably is added at room temperature (about 23° C.) and theresulting mixture is heated to about 100° C. giving a crude mixture ofbiotin ester V.

After distillation of the solvent, the crude mixture of biotin ester Vcan be subjected directly to hydrolysis which yields biotin Va. Thehydrolysis is carried out in any conventional manner. A suitable methodincludes treatment of crude mixture V with an alkali metal hydroxide(e.g., sodium hydroxide). Conventional temperature ranges for hydrolysisare utilized.

If desired, compounds IV, IVa, V and Va can be resolved into theirstereoisomers by conventional resolution techniques.

In accordance with another aspect of the invention, compound I, used asa starting material in Reaction Scheme 1, is prepared from 2H-chromeneof the formula: ##STR11## by the following reaction scheme: ##STR12##wherein R⁴ is hydrogen; R^(4') is --SO₂ N₃ ; and R⁵ is --SO₂ Cl.

In accordance with Reaction Scheme 2, 2H-chromene of formula VI isreacted with chlorosulphonylisocyanate to give compound VII wherein R⁵is --SO₂ Cl.

This reaction is preferably carried out in an inert organic solvent(e.g., a chlorinated hydrocarbon such as methylene chloride orchloroform, or an ether such as tetrahydrofuran).

The reaction is initially carried out at the lowest temperaturespossible, namely at temperatures between -60° C. and -35° C. Theresulting reaction mixture is left to stand (for example, for 3 hours at-60° C.), then within 4 hours is allowed to warm to -35° C. andsubsequently is left overnight at this temperature. There is obtainedcompound VII wherein R⁵ is --SO₂ Cl.

Compound VII is converted into compound VIII wherein R^(4') isazidosulphonyl (i.e., --SO₂ N₃), in a sodium azide/triethylammoniumazide/hydrazoic acid system. The reaction preferably proceeds in aninert organic solvent (e.g., a halogenated hydrocarbon such as methylenechloride or chloroform) and at low temperatures. Preferred temperaturesare about -10° C. to about -20° C.

Compound VIII is converted into compound IX by a Curtius degradation.That is, compound VIII is heated in an organic solvent (e.g., toluene orbenzene) at about 60°-100° C., preferably to about 80° C. to yieldcompound IX.

Compound IX, wherein R^(4') is --SO₂ N₃, can be converted into compoundI, wherein R⁴ is hydrogen, by cleavage of the azidosulphonyl group ofcompound IX.

The cleavage of the azidosulphonyl group can be carried out by anyconventional cleaving method. For example, compound IX can be heated toboiling in the presence of an alkali metal sulphite (e.g., sodiumsulphite) in aqueous solution. Alternatively, hydrogen sulphide can alsobe used in place of the alkali metal sulphite.

Compounds I and IX can be collectively represented as a compound of theformula: ##STR13## wherein R^(4a) is hydrogen or azidosulphonyl.

In accordance with a further aspect of the invention, compound VIIwherein R⁵ is --SO₂ Cl can be converted to a corresponding compoundwherein R⁵ is hydrogen. The conversion occurs by reductive removal ofthe chlorosulphonyl group of compound VII using sodium iodide and sodiumbicarbonate.

The following Examples further illustrate the invention. Alltemperatures are in degrees Centigrade, unless otherwise stated. Roomtemperature is approximately 23° C. Ether connotes diethyl ether.Petroleum ether connotes the mixture of hydrocarbons of the methaneseries, principally pentanes and hexanes boiling between about 35° and80° C.

EXAMPLE 1

5.71 g of3a,9b-cis-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-d]imidazol-2-one and 1.38g of lithium amide are suspended in 45 ml of ethylamine in a 200 mlround flask. The round flask is attached via a head to a condenser whichis cooled to -50° C. by means of a cryostat.

The apparatus is flushed with nitrogen (dried over potassium hydroxide)and the suspension is stirred magnetically under reflux for 4 hours.1.67 g of 3 mm lithium wire (rinsed for a short time with nitrogen) areadded through the head and the mixture is stirred for 10 minutes. Thereare then added, at intervals of 10 minutes under nitrogen and withoutinterrupting the stirring, 10 ml, 10 ml, 30 ml and 30 ml portions ofdimethylamine. The mixture is stirred for 14 hours and then, in order todecolourise the deep blue mixture and in order to remove unreactedlithium, filtered through a filter packed with glass wool. After removalof the amine (nitrogen atmosphere), the yellowish residue is treatedwith 100 g of ice and stirred for 0.5 hour. After filtration of theprecipitated product, concentration and saturation of the mother liquorwith ammonium sulphate and renewed filtration, the entire material onthe filter is washed three times with 10 ml of cold water, dried andrecrystallized from 200 ml of methanol. After concentration of themother liquor and drying (24 hours at 80° C. and 0.01 mm), there areobtained 3.7 g of3a,9b-cis-1,2,3,3a,4,6,7,8,9,9b-decahydro-chromeno[3,4-d]-imidazol-2-oneof melting point 257°-260° C.

EXAMPLE 2

3.94 g of the decahydro compound of Example 1 are suspended in 70 ml ofwater, 3 ml of acetonitrile and 5 ml of ether in a 250 ml round flask.4.1 g of m-chloroperbenzoic acid in 50 ml of ether are slowly addeddropwise (during 2 hours) to the resulting suspension at roomtemperature with vigorous stirring. After completion of the addition,the phases are separated in a separating funnel, the aqueous phase isextracted three times with 30 ml of ether, the combined ether phases areextracted once with 5 ml of water and the aqueous phase is subsequentlyfreed from solvent residues on a rotary evaporator. This aqueoussolution is cooled to 0° C. and added to an ice-cold solution of 4.33 gof sodium periodate in 40 ml of water. The mixture is left to stand at0° C. for 2 hours, warmed to room temperature and held at thistemperature for 2 hours. After filtering off the crystallized-outproduct, the filtrate is concentrated to 40 ml. After renewedfiltration, the entire product is recrystallized from water. Includingthe product obtained after concentration of the mother liquor, there areobtained, after drying over phosphorus pentoxide (10 hours at 60° C. and0.01 mm), 3.65 g of1,10-cis-3-oxa-11,13-diazabicyclo[8.3.0]tridecane-4,9,12-trione ofmelting point 215°-230° C. (decomposition).

EXAMPLE 3

1 g of finely powdered1,10-cis-3-oxa-11,13-diazabicyclo[8.3.0]tridecane-4,9,12-trione isstirred at room temperature for 2 hours in 60 ml of absolute methanolwith 0.24 g of sodium borohydride in the presence of 0.7 g of molecularsieve 3 Å and then the mixture is left to stand for 7 hours. Afterfiltration the pH value of the solution is brought to 4.7 with glacialacetic acid and the solvent is distilled off. The residue is treatedthree times with 15 ml of absolute methanol each time and the methanolis in each case evaporated off and subsequently the residue is treatedwith 20 ml of absolute methanol. After distillation of the methanol atnormal pressure, solvent remains are removed on a rotary evaporator. Theresidue is treated with 5 ml of saturated ammonium sulphate solution,crystallisation occurring. The product obtained is filtered off, driedand recrystallised from a small amount of methanol. There is obtained0.73 g of a mixture of (εR,4 S,5S) and(εS,4R,5R)-5-hydroxymethyl-2-oxo-ε-hydroxy-4-imidazolidinecaproic acidmethyl ester of melting point 165°-167° C. (from methanol).

EXAMPLE 4

0.3 g of the crude mixture of Example 3 is dissolved in 5 ml of absolutepyridine and the solution is cooled to -10° C. 1.32 g ofmethanesulphonic acid chloride are added dropwise to the solution whilestirring and with exclusion of moisture, the temperature is held at -10°C. for a further 10 minutes and subsequently the mixture is stirred atroom temperature for a further 2 hours. The majority of the pyridine isthen distilled off at room temperature under a pressure of 0.05 mm andthe residue is triturated with 10 ml of petroleum ether (boiling point40°-50° C.). The petroleum ether phase is decanted off and the residueis freed from petroleum ether remains at a pressure of 0.05 mm. Afterthe addition of 5 g of ice, the mixture is extracted three times with 10ml of methylene chloride. After washing with three 3 ml portions of 2 Nhydrochloric acid and with one 5 ml portion of ice-water, the combinedmethylene chloride extracts are dried over sodium sulphate. Afterfiltration, the methylene chloride is distilled off on a rotaryevaporator and the residue, (εR,4S,5S)- and(εS,4R,5R)-5-methylsulphonyloxymethyl-2-oxo-ε-methylsulphonyloxy-4-methazolidinecaproicacid methyl ester, is dried at reduced pressure under room temperature.

EXAMPLE 5

The crude mixture of (εR,4S,5S)- and(εS,4R,5R)-5-methylsulphonyloxymethyl-2-oxo-ε-methylsulphonyloxy-4-methazolidinecaproicacid methyl ester (0.34 g) obtained according to Example 4 is dissolvedin 5 ml of hexamethylenephosphoric acid triamide and the solution isde-gassed with nitrogen. 0.21 g of sodium sulphide (Na₂ S.9H₂ O) areadded to the solution at room temperature while stirring and theresulting solution is heated to 100° C. within 30 minutes undernitrogen. After stirring at 100° C. for 2 hours, the majority of thehexamethylenephosphoric acid triamide is distilled off on a water-bathat 0.01 mm. The yellow residue is triturated with 20 ml of petroleumether (boiling point 40°-50° C.) and the petroleum ether phase isdecanted off. After the removal of petroleum ether residues on a rotaryevaporator, the residue is taken up in 100 ml of 2 N sodium hydroxide,treated with 0.2 g of active carbon and heated on a boiling water-bathfor 3 hours. The hot solution is filtered, the filtrate is brought to apH value of 3 with concentrated hydrochloric acid, concentrated to 3 mland cooled at 0° C. for 30 minutes. The supernatant solution is decantedoff from the precipitated product and the latter is again heated underreflux for 15 minutes with 10 ml of water and 0.1 g of active carbon.After filtration, the filtrate is concentrated to 3 ml and cooled in anice-bath for 1 hour. The thus-obtained flocculent, yellowish product isfiltered off, pressed dry and taken up in 3 ml of boiling methanol.After trituration and filtration, the thus-obtained almost colourlessproduct is recrystallised from a small amount of water. After dryingover phosphorus pentoxide (at 80° C. and 0.05 mm for 14 hours), thereare obtained colourless, needle-like crystals of (±) biotin of meltingpoint 236°-237° C.

The methyl ether of this compound melts at 132°-134° C.

The reduction of3a,9b-cis-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-d]imidazol-2-one to give3a,9b-cis-1,2,3,3a,4,6,7,8,9,9b-decahydro-chromeno[3,4-d]imidazol-2-onecan be carried out, instead of in one-step as described in Example 1,but also in two-steps, the corresponding octahydro compound beingobtained in the first step. This two-step reduction can be carried outas described in Examples 6 and 7.

EXAMPLE 6

A suspension of 2 g of3a,9b-cis-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-d]imidazol-2-one in 150ml of liquid ammonia is treated with 6 g of potassium tert.butoxide andthe mixture is stirred for 0.5 hour. After the addition of 30 ml oftert.butanol, there is gradually introduced over a period of 60 minutes0.8 g of lithium which has been cut into 25 mg portions. The addition ofthe lithium should be carried out at such a rate that, during the entirereaction period, the mixture is blue in colour. After completion of theaddition of the lithium and as soon as the blue colour of the mixturehas disappeared, 150 ml of absolute methanol are added in order todecompose the tert.butoxide present. After distillation of the ammonia,100 g of ice are added to the methanolic residue and the methanol isdistilled off completely on a rotary evaporator. The productprecipitating from the solution (cooled to 0° C.) is, after filtration,washed three times on the filter with 25 ml of ice-water. After drying,the crude product is recrystallised from a small amount of acetonitrilecontaining 0.25 g of maleic acid anhydride. After drying (14 hours at25° C. and 0.01 mm), there are obtained 1.4 g of3a,9b-cis-1,2,3,3a,4,6,9,9b-octahydro-chromeno[3,2-d]-imidazol-2-one ofmelting point 253°-255° C. (from methanol).

EXAMPLE 7

0.1 g of3a,9b-cis-1,2,3,3a,4,6,9,9b-octahydro-chromeno[3,2-d]-imidazol-2-onedissolved in 22 ml. of absolute methanol, is added at 20° C. in ahydrogen atmosphere (770 mmHg) to 20 mg of platinum oxide in 5 ml. ofabsolute methanol. The mixture is stirred and the calculated amount ofhydrogen is taken up within 10 minutes. After 15 minutes, thehydrogenation is interrupted, the catalyst is filtered off and thesolvent is removed on a rotary evaporator. The crystalline residue,3a,9b-cis-1,2,3,3a,4,6,9,9b-decahydro-chromeno[3,2-d]-imidazol-2-one,melts at 250°-253° C.

The 3a,9b-cis-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-d]imidazol-2-one usedas the starting material in Examples 1 and 6 can be prepared asdescribed in following Examples 8-11.

EXAMPLE 8

14.2 g of chlorosulphonylisocyanate are cooled with liquid nitrogen in a100 ml round flask (fitted with a drying tube charged with calciumchloride and phosphorus pentoxide) until the chlorosulphonylisocyanatesolidifies. 13.1 g of 2H-chromene and 6.5 ml of absolute ether are thenrapidly added, a light red colouration occurring. The mixture is thenimmediately cooled with liquid nitrogen for 10 minutes. Subsequently,the vessel is left to stand at -60° C. for 3 hours, then warmed within 4hours to -35° C. and left to stand at -35° C. overnight (16 hours). Themixture is then warmed to -25° C. for 4 hours and again cooled to -35°C., the flask content solidifying to a light yellowish-red colouredcrystal mass which consists of crude1-chlorosulphonyl-2,3,4,10-tetrahydro-1H-chromeno[3,4-c]azet-2-one.(N-chlorosulphonyl-β-lactam).

From 1-chlorosulphonyl-2,3,4,10-tetrahydro-1H-chromeno[3,4-c]azet-2-one,there can be obtained by reductive removal of the chlorosulphonyl groupusing sodium iodide and sodium bicarbonate the compound of formula VIIin which R⁵ is hydrogen. The latter compound melts at 196°-197.5° C.(from chloroform).

EXAMPLE 9

For the further reduction of N-chlorosulphonyl-β-lactam of Example 8there is required a buffer system which is prepared as follows:

To a suspension, prepared while stirring, of 27.3 g of sodium azide,27.6 g of water and 80 ml of methylene chloride are slowly addeddropwise, after cooling to 0° C., 20.58 g of concentrated sulphuric acidso that the temperature does not rise above +10° C. After completion ofthe addition, the mixture is stirred at 0° C. for a further 20 minutes,decanted off from precipitated sodium sulphate and the residue is washedfour times with 10 ml of methylene chloride each time. 21.5 g oftriethylamine are introduced while stirring into the combined decantateswhich are dried over sodium sulphate and cooled to -20° C. by externalcooling, whereby the internal temperature should not rise above -8° C.

EXAMPLE 10

50 ml of absolute methylene chloride are added to crude1-chlorosulphonyl-2,3,4,10-tetrahydro 1H-chromeno[3,4-c]azet-2-one(N-chlorosulphonyl-β-lactam), of Example 8, and as large as possibleamount of the lactam is dissolved at -10° C. The thus-obtained solutionis added dropwise to the buffer system, of Example 9 held at -20° C. sothat the temperature remains between -18° C. and -16° C. Aftercompletion of the addition, 30 ml of methylene chloride are added to thestill undissolved lactam, this is dissolved at 0° C. and the solutionobtained is again added dropwise to the buffer system. After completionof the addition, the mixture is warmed to room temperature within 30minutes while stirring and then treated with 100 ml of ice-water. The pHvalue of the aqueous phase is brought to 3.5 with concentratedhydrochloric acid with vigorous stirring. After separation of thephases, the methylene chloride phase is washed three times with 50 ml ofcold water. After drying over sodium sulphate and filtration, themethylene chloride is distilled off at room temperature on a rotaryevaporator. The thus-obtained bis-azide of formula VIII in which R⁴represents the azidosulphonic group is a yellowish, semicrystalline tooily substance. It is taken up in 200 ml of absolute toluene and heatedat 85° C. on a water-bath. Nitrogen evolution occurs and, after a shorttime, a voluminous needle-like precipitate begins to separate out. It isthereupon heated for a further 15 minutes while shaking on a boilingwater-bath, subsequently cooled to room temperature and left to standfor 0.5 hour. The precipitate is filtered off and washed on the filterfour times with 10 ml of ice-cold methanol. After drying (3 hours at 60°C. and 0.1 mm), there are obtained 16.5 g of3a,9b-cis-1-azidosulphonyl-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-d]imidazol-2-onein the form of colourless needles of melting point 195° C. Afterrecrystallisation from methanol, the compound melts at 191°-192° C.

EXAMPLE 11

27.2 g of the azidosulphonyl compound of Example 10, 23.2 g of sodiumsulphite and 500 ml of water are boiled under reflux in a 4 liter flaskfor 35 minutes while shaking. Upon cooling, crystallisation sets in andis completed at 0° C. The precipitate is filtered off and washed with 50ml of cold water. Further product is obtained by concentrating themother liquor to 80 ml, analogous crystallisation and washing withwater. After drying over phosphorus pentoxide (4 hours at 80° C. and 0.1mm), there are obtained 17.3 g of 3a,9b cis1,2,3,3a,4,9b-hexahydro-chromeno[3,4-d]imidazol-2-one of melting point265° C. (from water). After recrystallisation from ethanol, the compoundmelts at 260°-263° C.

We claim:
 1. A compound of the formula ##STR14## wherein R⁵ is --SO₂ Cl.